Approximately 15% to 25% of patients infected with human immunodeficiency virus (HIV) also develop a rare neoplasm, Kaposis Sarcoma (KS). It has been shown that a novel herpesvirus, Kaposis Sarcoma-associated Herpesvirus (KSHV) is the infective agent that causes KS. All herpesviruses mature through the same lifecycle, which involves a crucial virally encoded protease. The protease from KSHV has been isolated and expressed. KSHV Pr, like all other known herpesviral proteases, functions as a homodimer. Our lab has characterized an autolysis site within KSHV Pr which releases 27 carboxyl terminal amino acids and which causes the protease to be unable to dimerize and to be inactive. We are studying the inactive monomeric truncated enzyme, KSHV Pr delta. Using nuclear magnetic resonance (NMR) we are determining the three dimensional structure of the protein. We are also using molecular biology to systematically rebuild the truncated carboxyl terminal fragment back into the protein to determine which residues are important for specific functions. The immediate goal of this research is to determine the structural changes that KSHV Pr undergoes upon inactivation. The eventual goal is to determine the conformational changes that KSHV Pr undergoes during the monomer to dimer transition. This would allow us to use the dimer interface as a therapeutic target. The resources of the Computer Graphics Laboratory allow us to rationally design mutants and variants of KSHV Pr as well as allowing us to do homology modeling between the different herpesviral proteases.